DESCRIPTION: Painful bladder syndrome/interstitial cystitis (PBS/IC) is a disease with unknown etiology, which presents clinically as urinary urgency, frequency, and bladder associated pain. PBS/IC has a devastating psychological and social impact on quality of life, and currently has no effective treatment. The clinical challenge for diagnosis and treatment of PBS/IC is certainly a reflection of the lack of basic scientific knowledge about bladder nociception, i.e., its peripheral origination, transmission, and central nervous system mechanisms. Although basic scientific studies have revealed the important role of the parasympathetic (pelvic nerve) C-fiber afferent pathway in bladder nociception, little is known about the role of the sympathetic (hypogastric nerve) afferent pathway that also innervates the bladder and generates afferent firing during bladder distension/irritation. However, clinical reports showed that blockade of the sympathetic afferent pathway could significantly relieve visceral pelvic pain including PBS/IC symptoms. Furthermore, bladder sensation/pain could still be elicited in human subjects with destroyed sacral spinal cord or transected sacral spinal roots, indicating an important role of sympathetic afferent pathways. In this grant application we will focus our studies on the sympathetic afferent pathway to close the gap between clinical evidence and basic scientific knowledge about bladder nociception. Our studies will determine the function of the sympathetic afferent pathway in bladder control and nociception, determine the properties of chemo-sensitive sympathetic nociceptive bladder afferent fibers, and define the brain projections of these afferents. A new nociceptive bladder reflex from hypogastric afferent nerves to pelvic efferent nerves will be analyzed for the first time. These studies will open a new field of research and dramatically change our current understanding of bladder overactivity, frequency, urgency, incontinence, and more importantly bladder nociception. Determining the role of the sympathetic afferent pathway in bladder nociception will promote the development of new diagnostic methods and effective treatments targeting the neurotransmitters/receptors in this pathway. The success of our proposed studies will significantly benefit millions of Americans suffering from PBS/IC.